Substituted tetrahydropyridines as central nervous system agents

ABSTRACT

Substituted tetrahydropyridines and derivatives thereof are described, as well as methods for the preparation and pharmaceutical composition of same, which are useful as central nervous system agents and are particularly useful as dopaminergic, antipsychotic, and antihypertensive agents as well as for treating hyperprolactinaemia-related conditions and central nervous system disorders.

This is a divisional application of U.S. Ser. No. 07/585,758 filed Sep.20, 1990, now U.S. Pat. No. 5,045,550.

BACKGROUND OF THE INVENTION

The present invention relates to novel substituted tetrahydropyridinesand derivatives thereof useful as pharmaceutical agents, to methods fortheir production, to pharmaceutical compositions which include thesecompounds and a pharmaceutically acceptable carrier, and topharmaceutical methods of treatment. The novel compounds of the presentinvention are central nervous system agents. More particularly, thenovel compounds of the present invention are dopaminergic agents.

A series of pyridine derivatives of the formula ##STR1## wherein R¹ andR² are independently each phenyl or 2- or 3-thienyl radicals which areunsubstituted or monosubstituted or disubstituted by alkyl, alkoxy, F,Cl, Br, OH, and/or CF₃ and n is 1, 2, or 3, and the alkyl and alkoxygroups each have 1-4 C atoms and salts thereof having suppressantactions on the central nervous system is disclosed in U.S. Pat. No.4,665,187.

However, the compounds disclosed in the aforementioned references do notdisclose or suggest the combination of structural variations of thecompounds of the present invention described hereinafter.

SUMMARY OF THE INVENTION

Accordingly, the present invention is a compound of Formula I ##STR2##wherein R is ##STR3## X is ##STR4## or --CH₂ --; n is an of 2 to 4;

R¹ is aryl, 2- or 3-1H-indolyl, or 2- or 3-1H-indolyl substituted bylower alkyl, lower alkoxy, or halogen, 2-, 3-, or 4-pyridinyl, or 2-,3-, or 4-pyridinyl substituted by lower alkyl, lower alkoxy, or halogen,2-, 4-, or 5-pyrimidinyl, or 2-, 4-, or 5-pyrimidinyl substituted bylower alkyl, lower alkoxy, or halogen, 2-pyrazinyl or 2-pyrazinylsubstituted by lower alkyl, lower alkoxy, or halogen, 2- or 3-thienyl,or 2- or 3-thienyl substituted by lower alkyl or halogen, 2- or3-furanyl, or 2- or 3-furanyl substituted by lower alkyl or halogen, 2-,4-, or 5-thiazolyl, or 2-, 4-, or 5-thiazolyl substituted by lower alkylor halogen; or a pharmaceutically acceptable acid addition salt thereof.

As dopaminergic agents, the compounds of Formula I are useful asantipsychotic agents for treating psychoses such as schizophrenia. Theyare also useful as antihypertensives and for the treatment of disorderswhich respond to dopaminergic activation. Thus, other embodiments of thepresent invention include the treatment, by a compound of Formula I, ofhyperprolactinaemia-related conditions, such as galactorrhea,amenorrhea, menstrual disorders and sexual dysfunction, and severalcentral nervous system disorders such as Parkinson's disease,Huntington's chorea, and depression.

A still further embodiment of the present invention is a pharmaceuticalcomposition for administering an effective amount of a compound ofFormula I in unit dosage form in the treatment methods mentioned above.

Finally, the present invention is directed to methods for production ofa compound of Formula I.

DETAILED DESCRIPTION OF THE INVENTION

In the compounds of Formula I, the term "lower alkyl" means a straightor branched hydrocarbon radical having from one to six carbon atoms andincludes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl,sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, and the like.

The term "aryl" means an aromatic radical which is a phenyl group orphenyl group substituted by one to four substituents selected from loweralkyl, lower alkoxy, lower thioalkoxy, halogen or trifluoromethyl suchas, for example, benzyl, phenethyl, and the like.

"Lower alkoxy" and "thioalkoxy" are O-alkyl or S-alkyl of from one tosix carbon atoms as defined above for "lower alkyl."

"Halogen" is fluorine, chlorine, bromine, or iodine.

"Alkali metal" is a metal in Group IA of the periodic table andincludes, for example, lithium, sodium, potassium, and the like.

"Alkaline-earth metal" is a metal in Group IIA of the periodic table andincludes, for example, calcium, barium, strontium, magnesium, and thelike.

"Noble metal" is platinum, palladium, rhodium, ruthenium, and the like.

Pharmaceutically acceptable acid addition salts of the compounds ofFormula I include salts derived from nontoxic inorganic acids, such ashydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydriodic,phosphorous, and the like, as well as the salts derived from nontoxicorganic acids, such as aliphatic mono- and dicarboxylic acids,phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioicacids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. Suchsalts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite,nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate,metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate,propionate, caprylate, isobutyrate, oxalate, malonate, succinate,suberate, sebacate, fumarate, maleate, mandelate, benzoate,chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate,benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate,maleate, tartrate, methanesulfonate, and the like. Also contemplated aresalts of amino acids such as arginate and the like and gluconate,galacturonate (see, for example, Berge, S. M., et al, "PharmaceuticalSalts," Journal of Pharmaceutical Science, Vol. 66, pages 1-19 (1977)).

The acid addition salts of said basic compounds are prepared bycontacting the free base form with a sufficient amount of the desiredacid to produce the salt in the conventional manner. The free base formmay be regenerated by contacting the salt form with a base and isolatingthe free base in the conventional manner. The free base forms differfrom their respective salt forms somewhat in certain physical propertiessuch as solubility in polar solvents, but otherwise the salts areequivalent to their respective free base for purposes of the presentinvention.

Certain of the compounds of the present invention can exist inunsolvated forms as well as solvated forms, including hydrated forms. Ingeneral, the solvated forms, including hydrated forms, are equivalent tounsolvated forms and are intended to be encompassed within the scope ofthe present invention.

A preferred compound of Formula I is one wherein R¹ is aryl, 2- or3-1H-indolyl, or 2- or 3-1H-indolyl substituted by lower alkyl, loweralkoxy, or halogen, 2-, 3-, or 4-pyridinyl or 2-, 3-, or 4-pyridinylsubstituted by lower alkyl, lower alkoxy, or halogen, 2-, 4-, or5-pyrimidinyl or 2-, 4-, or 5-pyrimidinyl substituted by lower alkyl,lower alkoxy, or halogen, 2- or 3-thienyl or 2- or 3-thienyl substitutedby lower alkyl or halogen.

Another preferred embodiment is a compound of Formula I wherein R¹ isaryl, 2- or 3-1H-indolyl, 2-, 3-, or 4-pyridinyl, 2-, 4-, or5-pyrimidinyl, or 2- or 3-thienyl.

Particularly valuable are:

4-(3,6-Dihydro-4-phenyl-1(2H)-pyridinyl)-1-(3-pyridinyl)-1-butanone;

3-[4-(3,6-Dihydro-4-phenyl-1(2H)-pyridinyl)-butyl]pyridine;

3-[4-[3,6-Dihydro-4-(2-thienyl)-1(2H)-pyridinyl]-butyl]pyridine;

4-(3,6-Dihydro-4-phenyl-1(2H)-pyridinyl)-1-(4-pyridinyl)-1-butanone;

4-[4-(3,6-Dihydro-4-phenyl-1(2H)-pyridinyl)-butyl]pyridine;

2-[1,2,3,6-Tetrahydro-1-[4-(4-pyridinyl)butyl]-4-pyridinyl]pyridine;

3-[1,2,3,6-Tetrahydro-1-[4-(4-pyridinyl)butyl]-4-pyridinyl]-1H-indole;

4-[4-[3,6-Dihydro-4-(2-thienyl)-1(2H)-pyridinyl]-butyl]pyridine;

4-[3-(3,6-Dihydro-4-phenyl-1(2H)-pyridinyl)-propyl]pyridine;

4-[5-(3,6-Dihydro-4-phenyl-1(2H)-pyridinyl)-pentyl]pyridine;

3-[4-(3,6-Dihydro-4-phenyl-1(2H)-pyridinyl)-butyl]quinoline;

3-[4-[3,6-Dihydro-4-(2-pyridinyl)-1(2H)-pyridinyl]butyl]quinoline;

2-[1,2,3,6-Tetrahydro-1-[4-(3-pyridinyl)butyl]-4-pyridinyl]pyridine;

4-(3,6-Dihydro-4-phenyl-1(2H)-pyridinyl)-1-(3-quinolinyl)-1-butanone;

3-[3-[3,6-Dihydro-4-(2-thienyl)-1(2H)-pyridinyl]propyl]quinoline;

3-[3-(3,6-Dihydro-4-phenyl-1(2H)-pyridinyl)-propyl]quinoline;

3-[5-[3,6-Dihydro-4-(2-thienyl)-1(2H)-pyridinyl]-butyl]quinoline;

3-[5-(3,6-Dihydro-4-phenyl-1(2H)-pyridinyl)-pentyl]quinoline; and

3-[5-(3,6-Dihydro-4-(2-thienyl)-1(2H)-pyridinyl]-pentyl]quinoline;

or a pharmaceutically acceptable acid addition salt thereof.

The compounds of Formula I are valuable dopaminergic agents. The testsemployed indicate that compounds of Formula I possess dopaminergicactivity. Thus, the compounds of Formula I were tested for their abilityto inhibit locomotor activity in mice according to the assay describedby J. R. McLean, et al, Pharmacology, Biochemistry and Behavior, Volume8, pages 97-99 (1978); for their ability to inhibit [³ H]-spiroperidolbinding in a receptor assay described by D. Grigoriadis and P. Seeman,Journal of Neurochemistry, Volume 44, pages 1925-1935 (1985); and fortheir ability to inhibit dopamine synthesis in rats according to theprotocol described by J. R. Walters and R. H. Roth,Naunyn-Schmiedeberg's Archives of Pharmacology, Volume 296, pages 5-14(1976). The above test methods are incorporated herein by reference. Thedata in the table show the dopaminergic activity of representativecompounds of Formula I.

                                      TABLE 1                                     __________________________________________________________________________    Biological Activity of Compounds of Formula I                                                                % Reversal                                                           Inhibition                                                                             of Brain                                                             of Locomotor                                                                           Dopamine                                                                             Inhibition of                                                 Activity Synthesis                                                                            [.sup.3 H]Spiroperidol                  Example               in Mice  in Rats at                                                                           Binding                                 Number                                                                             Compound         ED.sub.50, mg/kg, IP                                                                   10 mg/kg, IP                                                                         IC.sub.50, μM                        __________________________________________________________________________    9    4-(3,6-Dihydro-4-phenyl-1(2 .sub.-- H)-                                                        1.1      50    --                                            pyridinyl)-1-(3-pyridinyl)-                                                   1-butanone                                                               12   3-[4-(3,6-Dihydro-4-phenyl-                                                                    0.28     80    0.17                                          1(2 .sub.-- H)-pyridinyl)butyl]pyridine                                  8    3-[4-[3,6-Dihydro-4-(2-thienyl)-                                                               0.66     71    1.29                                          1(2 .sub.-- H)-pyridinyl]butyl]pyridine                                  10   4-(3,6-Dihydro-4-phenyl-1(2 .sub.-- H)-                                                        1.0      57    0.408                                         pyridinyl)-1-(4-pyridinyl)-                                                   1-butanone                                                               1    4-[4-(3,6-Dihydro-4-phenyl-1(2H)-                                                              0.6      87    0.096                                         pyridinyl)butyl]pyridine                                                 2    2-[1,2,3,6-Tetrahydro-1-[4-(4-                                                                 0.7      88    0.448                                         pyridinyl)butyl]-4-pyridinyl]-                                                pyridine                                                                 3    3-[1,2,3,6-Tetrahydro-1-[4-                                                                    5.0      --    0.398                                         (4-pyridinyl)butyl]pyridinyl]]-                                               1 .sub.-- H-indole                                                       4    4-[4-[3,6-Dihydro-4-(2-thienyl)-                                                               1.2      --    0.69                                          1(2H)-pyridinyl]butyl]pyridine                                           5    4-[3-(3,6-Dihydro-4-phenyl-1(2H)-                                                              0.63     61    --                                            pyridinyl)propyl] pyridine                                               7    4-[5-(3,6-Dihydro-4-phenyl-1(2H)-                                                              0.90     --    --                                            pyridinyl)pentyl]pyridine                                                13   3-[4-(3,6-Dihydro-4-phenyl-1-(2 .sub.-- H)-                                                    0.37     100   0.046                                         pyridinyl)butyl]quinoline                                                15   3-[4-[3,6-Dihydro-4-(2-pyridinyl)]-                                                            0.14     --    --                                            1-(2 .sub.-- H)-pyridinyl]butyl]quinoline                                14   3-[5-[3,6-Dihydro-4-(2-thienyl)]-1-                                                            1.50     --    --                                            (2 .sub.-- H)-pyridinyl]butyl]quinoline                                  __________________________________________________________________________

A compound of Formula Ia ##STR5## wherein R is ##STR6## n is an integerof 2 to 4;

R¹ is aryl, 2- or 3-1H-indolyl, or 2- or 3-1H-indolyl substituted bylower alkyl, lower alkoxy, or halogen, 2-, 3-, or 4-pyridinyl, or 2-,3-, or 4-pyridinyl substituted by lower alkyl, lower alkoxy, or halogen,2-, 4-, or 5-pyrimidinyl, or 2-, 4-, or 5-pyrimidinyl substituted bylower alkyl, lower alkoxy, or halogen, 2-pyrazinyl or 2-pyrazinylsubstituted by lower alkyl, lower alkoxy, or halogen, 2- or 3-thienyl,or 2- or 3-thienyl substituted by lower alkyl or halogen, 2- or3-furanyl, or 2- or 3-furanyl substituted by lower alkyl or halogen, 2-,4-, or 5-thiazolyl, or 2-, 4-, or 5-thiazolyl substituted by lower alkylor halogen; or a pharmaceutically acceptable acid addition salt thereofmay be prepared by reacting a compound of Formula Ib ##STR7## wherein R,R¹, and n are as defined above with a reducing agent such as, forexample, hydrazine, in the presence of an alkaline catalyst such assodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxideand the like, and a solvent such as, for example, ethylene glycol andthe like, or amalgamated zinc and an acid such as, for example,concentrated hydrochloric acid and the like, optionally in the presenceof a solvent such as, for example, ethanol, acetic acid, dioxane,toluene and the like, or treating a compound of Formula Ib with hydrogenin the presence of a catalyst such as a noble metal, for example,palladium on charcoal in the presence of a solvent such as, for example,ethanol and the like to give a compound of Formula Ia. Preferably, thereaction is carried out with hydrazine in the presence of potassiumhydroxide and ethylene glycol.

Alternatively, a compound of Formula Ia may be prepared from a compoundof Formula II

    R--CH.sub.2 --(CH.sub.2).sub.n --L                         (II)

wherein L is a halogen, or a leaving group such as, for example,methanesulfonyloxy, toluenesulfonyloxy and the like, and R and n are asdefined above, and a compound of Formula III ##STR8## wherein R¹ is asdefined above in the presence of a base such as, for example, an alkalimetal or alkaline earth metal hydroxide, carbonate or bicarbonate, forexample, sodium hydroxide, sodium carbonate, sodium bicarbonate,potassium hydroxide, potassium carbonate, potassium bicarbonate and thelike in the presence of a solvent such as, for example, acetonitrile andthe like to give a compound of Formula Ia. Preferably, the reaction iscarried out in the presence of potassium bicarbonate and acetonitrile.

A compound of Formula Ib is prepared from a compound of Formula IV##STR9## wherein R, N, and L are as defined above and a compound ofFormula III using the methodology used to prepare a compound of FormulaIa from a compound of Formula II and a compound of Formula III.

Compounds of Formula II, Formula III, and Formula IV are either known orcapable of being prepared by methods known in the art.

The compounds of the present invention can be prepared and administeredin a wide variety of oral and parenteral dosage forms. It will beobvious to those skilled in the art that the following dosage forms maycomprise as the active component, either a compound of Formula I or acorresponding pharmaceutically acceptable salt of a compound of FormulaI.

For preparing pharmaceutical compositions from the compounds of thepresent invention, pharmaceutically acceptable carriers can be eithersolid or liquid. Solid form preparations include powders, tablets,pills, capsules, cachets, suppositories, and dispersible granules. Asolid carrier can be one or more substances which may also act asdiluents, flavoring agents, solubilizers, lubricants, suspending agents,binders, preservatives, tablet disintegrating agents, or anencapsulating material.

In powders, the carrier is a finely divided solid which is in a mixturewith the finely divided active component.

In tablets, the active component is mixed with the carrier having thenecessary binding properties in suitable proportions and compacted inthe shape and size desired.

The powders and tablets preferably contain from five or ten to aboutseventy percent of the active compound. Suitable carriers are magnesiumcarbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin,starch, gelatin, tragacanth, methylcellulose, sodiumcarboxymethylcellulose, a low melting wax, cocoa butter, and the like.The term "preparation" is intended to include the formulation of theactive compound with encapsulating material as a carrier providing acapsule in which the active component, with or without other carriers,is surrounded by a carrier, which is thus in association with it.Similarly, cachets and lozenges are included. Tablets, powders,capsules, pills, cachets, and lozenges can be used as solid dosage formssuitable for oral administration.

For preparing suppositories, a low melting wax, such as a mixture offatty acid glycerides or cocoa butter, is first melted and the activecomponent is dispersed homogeneously therein, as by stirring. The moltenhomogenous mixture is then poured into convenient sized molds, allowedto cool, and thereby to solidify.

Liquid form preparations include solutions, suspensions, and emulsions,for example, water or water propylene glycol solutions. For parenteralinjection liquid preparations can be formulated in solution in aqueouspolyethylene glycol solution.

Aqueous solutions suitable for oral use can be prepared by dissolvingthe active component in water and adding suitable colorants, flavors,stabilizing and thickening agents as desired.

Aqueous suspensions suitable for oral use can be made by dispersing thefinely divided active component in water with viscous material, such asnatural or synthetic gums, resins, methylcellulose, sodiumcarboxymethylcellulose, and other well-known suspending agents.

Also included are solid form preparations which are intended to beconverted, shortly before use, to liquid form preparations for oraladministration. Such liquid forms include solutions, suspensions, andemulsions. These preparations may contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

The pharmaceutical preparation is preferably in unit dosage form. Insuch form the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

The quantity of active component in a unit dose preparation may bevaried or adjusted from 1 mg to 1000 mg preferably 10 mg to 100 mgaccording to the particular application and the potency of the activecomponent. The composition can, if desired, also contain othercompatible therapeutic agents.

In therapeutic use as antipsychotic agents, the compounds utilized inthe pharmaceutical method of this invention are administered at theinitial dosage of about 1 mg to about 50 mg per kilogram daily. A dailydose range of about 5 mg to about 25 mg per kilogram is preferred. Thedosages, however, may be varied depending upon the requirements of thepatient, the severity of the condition being treated, and the compoundbeing employed. Determination of the proper dosage for a particularsituation is within the skill of the art. Generally, treatment isinitiated with smaller dosages which are less than the optimum dose ofthe compound. Thereafter, the dosage is increased by small incrementsuntil the optimum effect under the circumstances is reached. Forconvenience, the total daily dosage may be divided and administered inportions during the day, if desired.

The following nonlimiting examples illustrate the inventors' preferredmethods for preparing the compounds of the invention.

EXAMPLE 1

4-[4-(3,6-Dihydro-4-phenyl-1(2H)-pyridinyl)butyl]-pyridine

A mixture of 4-(4-pyridinyl)-1-butylchloride (Example A) (0.76 g, 4.47mmol), 1,2,3,6-tetrahydro-4-phenylpyridine (0.796 g, 5.0 mmol), andpotassium bicarbonate (1.0 g, 10 mmol) in 5 mL of acetonitrile areheated to reflux for 8 hours. The reaction is cooled to room temperatureand the acetonitrile removed in vacuo. The residue is partitionedbetween 50 mL of water and 50 mL of chloroform. The aqueous layer isextracted again with 50 mL of chloroform and the combined organicextracts are dried over sodium sulfate and the solvent removed in vacuo.The resulting residue is chromatographed on silica gel (2% to 3%methanol, 0.1% ammonia, chloroform) to obtain 1.10 g of4-[4-(3,6-dihydro-4-phenyl-1(2H)-pyridinyl)-butyl]pyridine as a whitesolid; mp 89°-90° C.

In a process analogous to Example 1 using appropriate startingmaterials, the corresponding compounds of Formula I (Examples 2 to 8)are prepared as follows:

EXAMPLE 2

2-[1,2,3,6-Tetrahydro-1-[4-(4-pyridinyl)butyl]-4-pyridinyl]pyridine; mp98°-99° C.

EXAMPLE 3

3-[1,2,3,6-Tetrahydro-1-[4-(4-pyridinyl)butyl]-4-pyridinyl]]-1H-indole;mp 177°-178° C.

EXAMPLE 4

4-[4-[3,6-Dihydro-4-(2-thienyl)-1(2H)-pyridinyl]-butyl]pyridine; mp86-87° C.

EXAMPLE 5

4-[3-(3,6-Dihydro-4-phenyl-1(2H)-pyridinyl)propyl]-pyridine; mp166°-168° C.

EXAMPLE 6

2-[1,2,3,6-Tetrahydro-1-[4-(3-pyridinyl)butyl]-4-pyridinyl]pyridine.

EXAMPLE 7

4-[5-(3,6-Dihydro-4-phenyl-1(2H)-pyridinyl)pentyl]-pyridine; mp125°-126° C.

EXAMPLE 8

4-[4-[3,6-Dihydro-4-(2-thienyl)-1(2H)-pyridinyl]-butyl]pyridine; mp44°-46° C.

EXAMPLE 9

4-(3,6-Dihydro-4-phenyl-1(2H)-pyridinyl)-1-(3-pyridinyl)-1-butanone

A solution of 4-chloro-3-(3-pyridinyl)-1-butanone (Example D) (17.8 g,0.097 mol), 4-phenyl-1,2,3,6-tetrahydropyridine (44.7 g, 0.281 mol), andpotassium iodide (0.8 g, 0.005 mol) are heated on a steam bath for 15minutes. The residue is taken up in chloroform (60 mL) and theprecipitate is filtered. The filtrate is evaporated in vacuo andpurified by column chromatography (silica gel, 2%methanol/dichloromethane). The major product is crystallized fromdiethyl ether to give 4.5 g of4-(3,6-dihydro-4-phenyl-1(2H)-pyridinyl)-1-(3-pyridinyl)-1-butanone as asolid; mp 64°-66° C.

In a process analogous to Example 9 using appropriate starting materialsthe corresponding compounds of Formula I (Examples 10 to 12) areprepared as follows:

EXAMPLE 10

4-(3,6-Dihydro-4-phenyl-1(2H)-pyridinyl)-1-(4-pyridinyl)-1-butanone; mp97°-98° C.

EXAMPLE 11

4-(3,6-Dihydro-4-phenyl-1(2H)-pyridinyl)-1-(3-quinolinyl)-1-butanone; mp106°-107° C.

EXAMPLE 12

3-[4-(3,6-Dihydro-4-phenyl-1(2H)-pyridinyl)butyl]-pyridine; mp 45°-46°C.

EXAMPLE 13

3-[4-(3,6-Dihydro-4-phenyl-1(2H)-pyridinyl)butyl]-quinoline

A solution of 4-(3-quinolinyl)butan-1-ol (Example E) (2.0 g, 0.01 mol),N,N-diisopropylethylamine (3.5 mL, 0.02 mol) and a catalytic amount of4-dimethylaminopyridine is cooled to 0° C. and methanesulfonyl chloride(0.8 mL, 0.0105 mol) is added dropwise. The solution is stirred at 0° C.for 18 hours, and concentrated under reduced pressure. The residue istaken up in dimethylformamide (20 mL), and to this solution is added4-phenyl-1,2,3,6-tetrahydropyridine (2.41 g, 0.015 mol) and sodiumbicarbonate (3.4 g, 0.04 mol). The mixture is heated at 40° C. for 5hours and the solvent removed under reduced pressure. The residue ispartitioned between 50 mL of ethyl acetate and 50 mL of water. Theaqueous layer is extracted with 50 mL of ethyl acetate and the organicextracts are dried (sodium sulfate) and the solvent removed in vacuo.The residue is chromatographed (silica gel, 2% methanol/98%dichloromethane) to give 2.15 g of the title compound; mp 92.8°-93.9° C.

In a process analogous to Example 13 using appropriate startingmaterials the corresponding compounds of Formula I (Examples 14 to 19)are prepared as follows:

EXAMPLE 14

3-[5-[3,6-Dihydro-4-(2-thienyl-1(2H)-pyridinyl]-butyl]quinoline; mp73.8°-74.8° C.

EXAMPLE 15

3-[4-[3,6-Dihydro-4-(2-pyridinyl)-1(2H)-pyridinyl]-butyl]quinoline; mp81.2°-81.6° C.

EXAMPLE 16

3-[3-[3,6-Dihydro-4-(2-thienyl)-1(2H) pyridinyl]-propyl]quinoline.

EXAMPLE 17

3-[3-(3,6-Dihydro-4-phenyl-1(2H)-pyridinyl)propyl]-quinolinedihydrochloride salt; mp 166°-167° C.

EXAMPLE 18

3-[5-[3,6-Dihydro 4-(2-thienyl)-1(2H)-pyridinyl]- pentyl]quinoline.

EXAMPLE 19

3-[5-(3,6-Dihydro-4-phenyl-1(2H)-pyridinyl)pentyl]-quinolinedihydrochloride salt; mp 162°-163° C.

PREPARATION OF STARTING MATERIALS EXAMPLE A

4-(4-Pyridinyl)-1-butylchloride

A solution of 4-(4-pyridinyl)-1-butanol (Mayer J. M. and Testa, B.,Helv. Chim. Acta 65, pages 1868-1884 (1982)) (4.20 g, 27.7 mmol) in 30mL of chloroform is cooled to 0° C. and treated with thionyl chloride(6.60 g, 55.54 mmol) in 30 mL of chloroform. The reaction is allowed towarm to room temperature over 15 hours. The volatiles are removed invacuo. The residue is cooled to 0° C. and treated with 50 mL of cold 10%sodium hydroxide solution and the mixture is extracted with three 100-mLportions of chloroform. The combined organic extracts are dried oversodium sulfate and the solvents are removed under reduced pressure togive 4.25 g of 4-(4-pyridinyl)-1-butylchloride as a brown oil.

In a process analogous to Example A using appropriate starting materialsthe corresponding compound was prepared as follows:

EXAMPLE B

3-(4-Pyridinyl)-1-propylchloride (Mayer, J. M. and Testa, B., Helv.Chim. Acta, pages 1868-1884 (1982)).

EXAMPLE C

5-(4-Pyridinyl)-pentylchloride

Step A: Preparation of 4-(Chlorobutoxy)-3,4,5,6-2H-tetrahydropyran

A solution of 4-chlorobutanol (23.2 g, 0.2140 mol) and 2 drops ofconcentrated hydrochloric acid at 0° C. is treated with3,4-dihydro-2H-pyran (15 g, 0.1783 mol). The reaction is allowed to warmto room temperature over 3 hours. The reaction mixture is purified bydistillation (130° C., 20 mm) to give 18.07 g of2-(4-chlorobutoxy)-3,4,5,6-2H-tetrahydropyran as a colorless oil.

Step B: Preparation of 5-(4-Pyridinyl)-1-pentanol

Phenyl lithium (1.8 M cyclohexane diethyl ether, 27.6 mL, 0.0497 mol) isslowly added to a stirring solution of 4-picoline (4.6 g, 0.0497 mol) in50 mL of tetrahydrofuran under nitrogen. The solution is stirred for 20minutes at room temperature and then cooled to 0° C.2-(4-Chlorobutoxy)-3,4,5,6-2H-tetrahydropyran (6.4 g, 0.0332 mol) isslowly added to the reaction mixture and the mixture is stirred for 30minutes at 0° C. The reaction mixture is refluxed for 12 hours, cooled,and 100 mL of 10% hydrochloric acid solution is added. The reactionmixture is stirred for another 12 hours and then made basic with asaturated solution of sodium bicarbonate and extracted with chloroform.The organic phase is dried (sodium sulfate) and evaporated in vacuo. Theresulting residue is chromatographed on silica gel (ethyl acetate) togive 1.25 g of 5-(4-pyridinyl)-1 pentanol as a brown oil.

Step C: Preparation of 5-(4-pyridinyl)-1-pentylchloride

A solution of 5-(4-pyridinyl)-1-pentanol (3.71 g, 0.0225 mol) in 50 mLof chloroform is treated with thionyl chloride (5.4 g, 0.0449 mol) in 25mL of chloroform. The resulting solution is neutralized with a saturatedsolution of sodium bicarbonate and extracted with chloroform. Theorganic phase is dried (sodium sulfate) and evaporated in vacuo to give3.86 g of 5-(4-pyridinyl)-1-pentylchloride as a brown oil.

EXAMPLE D

4-Chloro-1-(3-pyridinyl)-1-butanone (Sato, M., et al, Chem. Pharm.Bull., 26, 3296 (1978)).

A solution of methyl nicotinate (59 g, 0.43 mol), 4-hydroxybutyric acidlactone (51.8 g, 0.602 mol), and sodium methoxide (70 g, 1.29 mol) indioxane (500 mL) is refluxed for 1 hour and then cooled. Concentratedhydrochloric acid (650 mL) is added, and the reaction mixture isrefluxed for 12 hours. The resulting solution is neutralized with solidsodium bicarbonate and extracted with chloroform. The organic phase isdried (sodium sulfate), and the solvent evaporated in vacuo. The residueis taken up in 2-propanol (50 mL) and treated with a saturated solutionof hydrogen chloride in 2-propanol. The hydrochloride salt of4-chloro-1-(3-pyridinyl)-1-butanone is obtained as a white solid (30 g);mp 73°-76° C.

EXAMPLE E

4-(3-Quinolinyl)butan-1-ol

Step A: Preparation of 4-(3-Quinolinyl)-3-butyn-1-ol

A solution of 3-bromoquinoline (13.57 mL, 0.10 mol) and 3-butyn-1-ol(9.0 mL, 0.12 mol) in 40 mL of triethylamine and 75 mL ofdichloromethane is degassed by bubbling dry nitrogen through it for 15minutes, and 0.7 g (0.001 mol) of bis(triphenylphosphine)palladiumdichloride and 0.013 g of cuprous iodide are added. The flask is flushedwith nitrogen and the mixture heated to reflux for 5 hours. The cooledmixture is diluted with dichloromethane and washed with water, dried(sodium sulfate), and concentrated to give 27 g of a gold oil. The oilwas triturated with diethyl ether to give 18.2 g of the title compoundas a tan solid; mp 95.7°-96.7° C.

Step B: Preparation of 4-(3-Quinolinyl)butan-1-ol

A solution of 4-(3-quinolinyl)-3-butyn-1-ol (17.0 g, 0.086 mol) ishydrogenated over palladium on carbon (1.0 g) in ethanol (400 mL) atroom temperature. After the catalyst is filtered, the solvent is removedunder reduced pressure to give 17.3 g of a brown oil. The oil ischromatographed (silica gel, 2% methanol/98% dichloromethane) to give13.5 g of the title compound as a yellow oil.

We claim:
 1. A compound of Formula I ##STR10## wherein R is ##STR11## Xis ##STR12## or --CH₂ --; n is an integer of 2 to 4;R¹ is aryl, 2- or3-1H-indolyl, or 2- or 3-1H-indolyl substituted by lower alkyl, loweralkoxy, or halogen, 2-, 3-, or 4-pyridinyl, or 2-, 3-, or 4-pyridinylsubstituted by lower alkyl, lower alkoxy, or halogen, 2-, 4-, or5-pyrimidinyl, or 2-, or 4-, or 5-pyrimidinyl substituted by loweralkyl, lower alkoxy, or halogen, 2-pyrazinyl or 2-pyrazinyl substitutedby lower alkyl, lower alkoxy, or halogen, 2- or 3-thienyl, or 2- or3-thienyl substituted by lower alkyl or halogen, 2- or 3-furanyl, or 2-or 3-furanyl substituted by lower alkyl or halogen, 2-, 4-, or5-thiazolyl, or 2-, or 5-thiazolyl substituted by lower alkyl orhalogen; or a pharmaceutically acceptable acid addition salt thereof. 2.A compound according to claim 1, in which R¹ is aryl, 2- 3-1H-indolyl,or 2- or 3-1H-indolyl substituted by lower alkyl, lower alkoxy, orhalogen, 2-, 3-, or 4-pyridinyl, or 2-, 3-, or 4-pyridinyl substitutedby lower alkyl, lower alkoxy, or halogen, 2-, 4-, or 5-pyrimidinyl, or2-, 4-, or 5-pyrimidinyl substituted by lower alkyl, lower alkoxy, orhalogen, 2- or 3-thienyl or 2- or 3-thienyl substituted by lower alkylor halogen.
 3. A compound according to claim 2, in which R¹ is aryl, 2-or 3-1H-indolyl, 2-, 3-, or 4-pyridinyl, 2-, 4-, or 5-pyrimidinyl, or 2-or 3-thienyl.
 4. A compound according to claim 3 selected from the groupconsistingof:3-[4-(3,6-Dihydro-4-phenyl-1(2H)-pyridinyl)-butyl]quinoline;3-[4-[3,6-Dihydro-4-(2-pyridinyl)-1-(2H)-pyridinyl]butyl]quinoline;4-(3,6-Dihydro-4-phenyl-1(2H)-pyridinyl)-1-(3-quinolinyl)-1-butanone;3-[3-[3,6-Dihydro-4-(2-thienyl)-1(2H)-pyridinyl]propyl]quinoline;3-[3-(3,6-Dihydro-4-phenyl-1(2H)-pyridinyl)-propyl]quinoline;3-[5-[3,6-Dihydro-4-(2-thienyl)-1-(2H)-pyridinyl]butyl]quinoline;3-[5-(3,6-Dihydro-4-phenyl-1(2H)-pyridinyl)-pentyl]quinoline; and3-[5-(3,6-Dihydro-4-(2-thienyl)-1(2H)-pyridinyl]-pentyl]quinoline.
 5. Amethod of treating schizophrenia comprising administering to a hostsuffering therefrom a therapeutic effective amount of a compoundaccording to claim 1 in unit dosage form.
 6. A pharmaceuticalcomposition adapted for administration as a dopaminergic, antipsychotic,antihypertensive or antidepressant agent comprising a therapeuticeffective amount of a compound according to claim 1 in admixture with apharmaceutically acceptable excipient, diluent or carrier.